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Abstract Background ST-elevation myocardial infarction (STEMI) is a common acute ischemia heart disease that causes serious damage to human health worldwide. Even though morbidity and mortality have significantly decreased by percutaneous coronary intervention (PCI), an additional cardiac protection strategy is still required. Acupuncture therapy has presented a dominant cardiac protection in many studies lately. Thus, we aim to evaluate the effect and safety of acupuncture as an adjunctive therapy in STEMI patients after PCI through a randomized controlled trial. Methods/Design This study describes a protocol of multicenter, double-blinded, parallel-controlled, randomized controlled trial. Ninety-six patients with STEMI aged 18–85 years who undergoing PCI will be recruited from the Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, The Affiliated Third Hospital of Chengdu Traditional Chinese Medicine University/Chengdu Pidu District Hospital of Traditional Chinese Medicine, and Zhaotong Municipal Hospital of Traditional Chinese Medicine. Participants will be randomly assigned (1:1 ratio) to the verum acupuncture plus basic therapy (i.e., treatment) group or the sham acupuncture plus basic therapy (i.e., control) group. These participants will be treated for 5 days and then will be followed up for 24 weeks. Any adverse events will be recorded throughout the study to evaluate safety. Discussion The present study aims to investigate the effect and safety of acupuncture for patients with STEMI after PCI and set up standardized treatment programs for acupuncture of these patients. Trial registration This study was registered in the Chinese Clinical Trial Registry (Registration ID: [ChiCTR2400081117]), on February 22, 2024.

Abstract Tumour metabolic reprogramming is pivotal for tumour survival and proliferation. Investigating potential molecular mechanisms within the heterogeneous and clinically aggressive triple-negative breast cancer (TNBC) subtype is essential to identifying novel therapeutic targets. Accordingly, we investigated the role of branched-chain α-keto acid dehydrogenase kinase (BCKDK) in promoting tumorigenesis in TNBC. We analysed The Cancer Genome Atlas dataset and immunohistochemically stained surgical specimens to investigate BCKDK expression and its prognostic implications in TNBC. The effects of BCKDK on tumorigenesis were assessed using cell viability, colony formation, apoptosis, and cell cycle assays, and subsequently validated in vivo. Metabolomic screening was performed via isotope tracer studies. The downstream target was confirmed using mass spectrometry and a co-immunoprecipitation experiment coupled with immunofluorescence analysis. Upstream transcription factors were also examined using chromatin immunoprecipitation and luciferase assays. BCKDK was upregulated in TNBC tumour tissues and associated with poor prognosis. BCKDK depletion led to reduced cell proliferation both in vitro and vivo. MYC-associated zinc finger protein (MAZ) was confirmed as the major transcription factor directly regulating BCKDK expression in TNBC. Mechanistically, BCKDK interacted with glucose-6-phosphate dehydrogenase (G6PD), leading to increased flux in the pentose phosphate pathway for macromolecule synthesis and detoxification of reactive oxygen species. Forced expression of G6PD rescued the growth defect in BCKDK-deficient cells. Notably, the small-molecule inhibitor of BCKDK, 3,6-dichlorobenzo(b)thiophene-2-carboxylic acid, exhibited anti-tumour effects in a patient-derived tumour xenograft model. Our findings hold significant promise for developing targeted therapies aimed at disrupting the MAZ/BCKDK/G6PD signalling pathway, offering potential advancements in treating TNBC through metabolic reprogramming.

Abstract Triple-negative breast cancer (TNBC) is more aggressive and has a higher metastasis rate compared with other subtypes of breast cancer. Due to the lack of drug-targetable receptors, chemotherapy is now the only available systemic treatment for TNBC. However, some patients might still develop drug resistance and have poor prognosis. Therefore, novel molecular biomarkers and new treatment targets are urgently needed for patients with TNBC. To provide molecular insights into TNBC progression, we investigated the function and the underlying mechanism of Defective in cullin neddylation 1 domain containing 5 (DCUN1D5) in the regulation of TNBC. By TCGA dataset and surgical specimens with immunohistochemical (IHC) staining method, DCUN1D5 was identified to be significantly upregulated in TNBC tumor tissues and negatively associated with prognosis. A series of in vitro and in vivo experiments were performed to confirm the oncogenic role of DCUN1D5 in TNBC. Overexpression of FN1 or PI3K/AKT activator IGF-1 could restore the proliferative and invasive ability induced by DCUN1D5 knockdown and DCUN1D5 could act as a novel transcriptional target of transcription factor Yin Yang 1 (YY1). In conclusion, YY1-enhanced DCUN1D5 expression could promote TNBC progression by FN1/PI3K/AKT pathway and DCUN1D5 might be a potential prognostic biomarker and therapeutic target for TNBC treatment.

Background: Glycolysis is an indispensable process for tumor cell,but the effect of glycolysis on the prognosis and immune cell infiltration of head and neck squamous cell carcinoma is not clear. Methods: Based on RNA bulk and single cell RNA sequencing data of head and neck squamous cell carcinoma from The Cancer Genome Atlas(TCGA) and GSE195832, the effect of glycolysis level on immune cell infiltration was analyzed. Then, we obtained the prognostic genes related to glycolysis through survival analysis to construct prognostic risk signature. Our sample and GSE65858 datasets are used as external verification datasets to verify the validity of the signature. Finally, we used Western blot and cell function assays to determine the relationship between risk genes and glycolysis and the function of prognostic genes. Result: The level of glycolysis was related to the prognosis of head and neck tumors (P = 0.0044). The results of immune infiltration analysis of TCGA database showed that high level glycolysis subgroup had less infiltration of macrophages, T cells and monocytes. Results of single cell sequencing analysis validates the above results. Additionally, Five risk genes(MUCL1,TRIML2,RAB3B,SPINK6,IGSF11) were selected to construct signature.Risk score was an independent prognostic factor(P < 0.01). The external validation set also shows the same result. In vitro functional and Western blot assays confirmed that the above five genes affect tumor function and related to the process of glycolysis. Conclusion: Glycolysis-related risk signatures can be used to predict the prognosis and immune infiltration of head and neck squamous cell carcinoma.

IntroductionThe programmed cell death (PCD) pathway plays an important role in restricting cancer cell survival and proliferation. However, limited studies have investigated the association between genetic variants in the 3′-untranslated region of the PCD pathway genes and breast cancer outcomes.MethodsIn this study, we genotyped 28 potentially functional single nucleotide polymorphisms (SNPs) in 23 PCD pathway genes in 1,177 patients with early-stage breast cancer (EBC) from a Han Chinese population. The median follow-up period was 174 months.ResultsAmong all the candidate SNPs, four independent SNPs (rs4900321 and rs7150025 in ATG2B, rs6753785 in BCL2L11, and rs2213181 in c-Kit) were associated with invasive disease-free survival (iDFS), distant disease-free survival (DDFS), breast cancer-specific survival (BCSS) and overall survival (OS), respectively. Further combined genotypes of these four SNPs revealed that the survival decreased as the number of unfavorable genotypes increased (Ptrend = 1.0 × 10−6, 8.5 × 10−8, 3.6 × 10−4, and 1.3 × 10−4 for iDFS, DDFS, BCSS, and OS, respectively). Receiver operating characteristic curve analysis demonstrated that incorporating unfavorable genotypes and clinicopathological variables improved the ability to predict EBC survival (P = 0.006, 0.004, 0.029, and 0.019 for iDFS, DDFS, BCSS, and OS, respectively). Additionally, rs6753785 and rs2213181 were associated with BCL2L11 and c-Kit mRNA expression, respectively.ConclusionsOur results suggest that these four SNPs may act as novel biomarkers for EBC survival, possibly by modulating the expression of the corresponding genes.

Abstract The PI3K/Akt signalling pathway is associated with the occurrence and development of tumours and significantly affects the prognosis of patients. We established a predictive signature based on the PI3K/Akt pathway to predict the prognosis of patients. The RNA-seq and clinical data of laryngeal cancer patients were downloaded from The Cancer Genome Atlas (TCGA) database. Three lncRNAs (MNX1-AS1, LINC00330, LSAMP-AS1) were selected through univariate, multivariate Cox and log-rank test analysis to establish a prognostic signature. The patients were then divided into high-risk and low-risk groups based on their risk score. In the TCGA training set, the survival time of the high-risk group was shorter than that of the low-risk group (P

Abstract Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor. Conventional treatments have not achieved breakthroughs in improving survival. Therefore, novel molecular targets and biomarkers need to be identified. As signal transduction docks on the cell membrane, tetraspanins (TSPANs) are associated with various tumors; however, research on their role in GBM remains extremely scarce. Gene expression and clinicopathological characteristic data were obtained from GEPIA, CGGA, HPA, cBioPortal, and GSCA databases to analyze the mRNA and protein expression levels, prognostic value, clinical relevance, mutation status, and targeted drug sensitivity of TSPANs in GBM. Gene set enrichment analysis (GSEA), Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used for biological process enrichment. Data from TCGA and TCIA were used to construct the tumor immune microenvironment landscape of TSPANs. Different R software algorithms were used to analyze the immune score, immune cell infiltration, and immune checkpoint correlation. Univariate and multivariate analyses were performed for TSPAN4, which had the most significant predictive prognostic value, and a nomogram model was constructed to predict individual outcomes. The expression and function of TSPAN4 were verified in vitro. TSPAN3/4/6/11/12/18/23/24/25/26/27/28/29/30/31expressions were significantly upregulated in GBM, and TSPAN3/4/6/11/18/24/25/26/29/30 were strongly correlated with prognosis. The expression of multiple TSPANs significantly correlated with 1p/19q co-deletion status, IDH mutation status, recurrence, age, and tumor grade. GSEA and GO analyses revealed the potential contribution of TSPANs in cell adhesion and migration. Immune correlation analysis revealed that TSPANs are related to the formation of the GBM tumor microenvironment (TME) and may influence immunotherapy outcomes. TSPAN4 is an independent prognostic factor and TSPAN4 knockdown has been demonstrated to strongly inhibit glioma cell proliferation, invasion, and migration in vitro. We comprehensively elaborated the prognostic value and potential role of differentially expressed TSPANs in GBM, including molecules that scientists have previously overlooked. This study provides a novel and comprehensive perspective on the pathological mechanisms of GBM and the future direction of individualized tumor immunotherapy, which may be a critical link between GBM malignant progression and TME remodeling.

Abstract Background Homeobox A (HOXA) family is involved in the development of malignancies as either tumor suppressors or oncogenes. However, their roles in glioblastoma (GBM) and clinical significance have not been fully elucidated. Methods HOXA mutation and expressions in pan-cancers were investigated using GSCA and Oncomine, which in GBM were validated by cBioPortal, Chinese Glioma Genome Atlas (CGGA), and The Cancer Genome Atlas (TCGA) datasets. Kaplan–Meier analyses were conducted to determine prognostic values of HOXAs at genetic and mRNA levels. Diagnostic roles of HOXAs in tumor classification were explored by GlioVis and R software. Independent prognostic HOXAs were identified using Cox survival analyses, the least absolute shrinkage and selection operator (LASSO) regression, quantitative real-time PCR, and immunohistochemical staining. A HOXAs-based nomogram survival prediction model was developed and evaluated using Kaplan–Meier analysis, time-dependent Area Under Curve, calibration plots, and Decision Curve Analysis in training and validation cohorts. Results HOXAs were highly mutated and overexpressed in pan-cancers, especially in CGGA and TCGA GBM datasets. Genetic alteration and mRNA expression of HOXAs were both found to be prognostic. Specific HOXAs could distinguish IDH mutation (HOXA1-7, HOXA9, HOXA13) and molecular GBM subtypes (HOXA1-2, HOXA9-11, HOXA13). HOXA1/2/3/10 were confirmed to be independent prognostic members, with high expressions validated in clinical GBM tissues. The HOXAs-based nomogram model exhibited good prediction performance and net benefits for patients in training and validation cohorts. Conclusion HOXA family has diagnostic values, and the HOXAs-based nomogram model is effective in survival prediction, providing a novel approach to support the treatment of GBM patients.

Abstract While overweight/obesity has become a major public health issue worldwide, any association between body mass index (BMI) and therapeutic response in neoadjuvant targeted therapy treated HER2 positive breast cancer patients remain unclear. The information from a total of four-hundred and ninety-one neoadjuvant targeted therapy treated HER2 positive breast cancer patients from four institutions were retrospectively collected. Univariate and multivariate logistic analysis was developed to determine the association between BMI and therapeutic response. A meta-analysis of published literature was then conducted to confirm the effect of overweight/obesity on pCR for patients treated with neoadjuvant targeted therapy. Restricted cubic spline (RCS) adjusted for confounding factors demonstrated a decrease pCR with increasing BMI (OR = 0.937, P = 0.045). Patients were then categorized into under/normal weight (n = 299) and overweight/obesity (n = 192). Overweight/obese patients were independently associated with a poor therapeutic response. In the subgroup analysis, a significant negative impact of overweight/obesity on pCR can be observed both in single-targeted (OR = 0.556; P = 0.02) and dual-targeted (OR = 0.392; P = 0.021) populations. Six eligible studies involving 984 neoadjuvant targeted therapy treated HER2 positive breast cancer patients were included in the meta-analysis. The meta-analysis also demonstrated that overweight/obesity was significantly associated with a poor response to neoadjuvant anti-HER2 therapy (OR = 0.68; P = 0.007). Our result show that overweight and obese HER2 positive breast cancer patients are less likely to achieve pCR after neoadjuvant targeted therapy.

ObjectiveWe aimed to evaluate the effects of different exercise rehabilitation (ER) programs on LVEF and the incidence of restenosis in patients after percutaneous coronary intervention (PCI) through a systematic review and an integrated network meta-analysis (NMA) to provide a reference for the clinical formulation of ER programs for PCI patients.MethodsMeta-analyses of the effects of different types of ER programs on LVEF and the incidence of reinfarction in post-PCI patients were retrieved from 11 domestic and foreign databases. The methodological and reporting quality of the included systematic reviews were evaluated using the AMSTAR 2 and PRISMA statements. The GRADE scoring system was used to evaluate the quality of evidence found in the studies included in the meta-analysis, and studies with high and intermediate-quality evidence were qualitatively analyzed. Stata software (version 16.0) was used to conduct an integrated NMA of the original RCTs with moderate and low risk of bias.ResultSixteen meta-analyses were included in this evaluation. The reporting quality of the included meta-analyses was relatively complete, and the methodological quality was low. Seventy RCTs were included in the NMA. The results showed that all types of rehabilitative exercises were safe and effectively increased LVEF and reduced the incidence of coronary restenosis in patients. The comprehensive exercise program was the most likely to improve LVEF, and the comprehensive exercise program, early exercise program, and high-intensity interval exercise were better than aerobic exercise. Comprehensive exercise programs, early exercise programs, and aerobic exercise reduced the incidence of restenosis in patients. However, Chinese Qigong did not reduce the incidence of restenosis in patients, and there was a risk of bias and inconsistency in the quantitative analysis of restenosis incidence.ConclusionComprehensive exercise programs have the greatest therapeutic significance in improving cardiac output and reducing restenosis rates in post-PCI patients. The early exercise program has great potential but requires kinesiologists to work with physicians to structure the program and strengthen out-of-hospital management. Aerobic exercise has the least therapeutic significance, and Chinese Qigong is suitable for promotion based on its better efficacy than aerobic exercise and may be an alternative to aerobic exercise, but more experimental evidence is needed.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, PROSPERO CRD42022374590.

Abstract Background Compelling evidence has indicated a significant association between leukocyte mitochondrial DNA copy number (mtDNAcn) and prognosis of several malignancies in a cancer-specific manner. However, whether leukocyte mtDNAcn can predict the clinical outcome of breast cancer (BC) patients has not been well investigated. Methods The mtDNA copy number of peripheral blood leukocytes from 661 BC patients was measured using a Multiplex AccuCopy™Kit based on a multiplex fluorescence competitive PCR principle. Kaplan–Meier curves and Cox proportional hazards regression model were applied to investigate the association of mtDNAcn with invasive disease-free survival (iDFS), distant disease-free survival (DDFS), breast cancer special survival (BCSS), and overall survival (OS) of patients. The possible mtDNAcn-environment interactions were also evaluated by the Cox proportional hazard regression models. Results BC patients with higher leukocyte mtDNA-CN exhibited a significantly worse iDFS than those with lower leukocyte mtDNAcn (5-year iDFS: fully-adjusted model: HR = 1.433[95%CI 1.038–1.978], P = 0.028). Interaction analyses showed that mtDNAcn was significantly associated with hormone receptor status (adjusted p for interaction: 5-year BCSS: 0.028, 5-year OS: 0.022), so further analysis was mainly in the HR subgroup. Multivariate Cox regression analysis demonstrated that mtDNAcn was an independent prognostic factor for both BCSS and OS in HR-positive patients (HR+: 5-year BCSS: adjusted HR (aHR) = 2.340[95% CI 1.163–4.708], P = 0.017 and 5-year OS: aHR = 2.446 [95% CI 1.218–4.913], P = 0.011). Conclusions For the first time, our study demonstrated that leukocyte mtDNA copy number might influence the outcome of early-stage breast cancer patients depending on intrinsic tumor subtypes in Chinese women.

据统计，2020年我国芝麻进口量达到历史高位，为101.61万 t，全国芝麻消费量保持增长态势，但在市场对芝麻的需求量扩大、市场前景广阔的背景下,广西芝麻的种植面积不增反降。为发挥广西芝麻种植优势，实现广西芝麻产业的高质量发展，详细论述了广西芝麻产业发展现状，分析了广西芝麻产业发展中存在的问题，并提出了发展对策。目前广西芝麻产业种植规模趋于稳定、种植品种类型多样、种植效益稳中有升、龙头企业引领市场,但仍然存在高产稳产品种不足,机械化生产能力薄弱,加工技术发展缓慢,产品销售渠道狭窄等问题。可通过加强良种技术攻关，提升器械应用水平，提高加工技术投入，拓宽产业市场渠道等对策，推动广西芝麻产业健康发展。 According to statistics，the import volume of sesame in China reached a historical high in 2020, with 1 016 100 t, and the national sesame consumption maintained a growth trend, but in the context of expanding market demand for sesame seeds and broad market prospects, the planting area of sesame in Guangxi decreased rather than increased. In order to give full play to the advantages of Guangxi′ sesame planting and realize the high-quality development of Guangxi′ sesame industry, the development status of Guangxi′ sesame industry was discussed in detail, the problems existing in the development of Guangxi′ sesame industry were analyzed, and countermeasures for development of Guangxi′ sesame industry were proposed. At present, the planting scale of Guangxi′ sesame industry tends to be stable, the types of planting varieties are diversified, the planting benefits are steadily rising, and leading enterprises lead the market, but there are still problems such as insufficient high-yielding and stable-yielding varieties, weak mechanized production capacity, slow development of processing technology, and narrow product sales channels. The healthy development of Guangxi′ sesame industry can be promoted by strengthening the technical research of improved variery, improving the application level of instruments,improving the investment in processing technology and broadening the market channels of the industry.

ObjectiveThis study aimed to investigate the accuracy and consistency of different ultrasound protocols for the measurement of gastrocnemius muscle (GM) thickness and to identify a suitable ultrasound scheme that can be used to detect the low muscle mass in older with disability.Materials and methodsIn this cross-sectional study, each participant underwent three different ultrasound protocols for the measurement of the GM thickness, and each measurement was repeated three times. The three measurement schemes were as follows: method A, lying on the examination bed in a prone position with legs stretched and relaxed and feet hanging outside the examination bed; method B, lateral right side lying position with legs separated (left leg flexed and right leg in a relaxed state); and method C, right side lying position with legs together and lower limb muscles in a relaxed state. The low muscle mass was determined by averaging two or three measurements of the GM thickness determined using different sonographic protocols.ResultsThe study included 489 participants. The difference in the prevalence of low muscle mass identified between two and three replicates of the same measurement protocol ranged from 0 to 1.3%. Considering the three repeated measurements of the method A as the reference, the area under the curve (AUC) in different measurement schemes were 0.977-1 and 0.973-1 in males and females, respectively. Furthermore, male and female Kappa values from low to high were 0.773, 0.801, 0.829, 0.839, and 0.967 and 0.786, 0.794, 0.804, 0.819, and 0.984, respectively.ConclusionDifferent ultrasound measurement protocols showed high accuracy and consistency in identifying low muscle mass. Repeating the measurements two or three times was found to be feasible.

Background Metabolic reprogramming is a key marker in the occurrence and development of tumors. This process generates more reactive oxygen species (ROS), promoting the development of oxidative stress. To prevent ROS from harming tumor cells, tumor cells can increase the production of reducing agents to counteract excessive ROS. NMRAL2P has been shown to promote the production of reductive mRNA and plays an important role in the process of oxidative stress. Methods In this study, the clinical data and RNA sequencing of head and neck tumors were obtained from The Cancer Genome Atlas data set. The long non-coding RNA (LncRNA) related to oxidative stress were then identified using differential and correlation analyses. The differential expression and prognosis of the identified lncRNA were then verified using samples from the library of the Second Hospital of Hebei Medical University. Only NMRAL2P was substantially expressed in cancer tissues and predicted a poor prognosis. The tumor-promoting impact of NMRAL2P was then confirmed using in vitro functional assays. The data set was then split into high- and low-expression subgroups based on the median gene expression of NMRAL2P to obtain the mRNA that had a large difference between the two groups, and examine the mechanism of NMRAL2P on GPX2 using quantitative real-time PCR, RNA binding protein immunoprecipitation assay, and chromatin immunoprecipitation. Mass spectrometry was used to identify NMRAL2P-binding proteins and western blotting was used to investigate probable mechanisms. Results The lncRNA NMRAL2P is associated with oxidative stress in head and neck tumors. In vitro functional assays showed that the gene has a cancer-promoting effect, increasing lactic acid and superoxide dismutase production, and reducing the production of ROS and malondialdehyde. NMRAL2P promotes the transcription of GPX2 by binding to transcription factor Nrf2. The gene also inhibits the degradation of ENO1, a crucial enzyme in glycolysis, by binding to protein ENO1. Conclusions This study shows that NMRAL2P can promote glycolysis and reduce the harm to tumor cells caused by ROS. The gene can also be used as a possible target for the treatment of head and neck tumors.

BackgroundPrevious epidemiological and other studies have shown an association between ischemic stroke (IS) and frozen shoulder (FS). However, the causal relationship between them remains unclear. Therefore, the present study aimed to investigate the causal relationship between IS and FS using a two-sample Mendelian randomization method.MethodsOur research was divided into two stages: discovery and replication. The data were extracted from publicly available genome-wide association studies (GWAS). We selected a large sample of IS (n = 440, 328) and its subtypes (large-artery atherosclerotic stroke (LAS), cardioembolic stroke (CES), and stroke caused by small-vessel disease (SVS) and lacunar stroke (n = 254, 959) as exposure data. Additionally, we selected a large sample of FS as outcome data (n = 451, 099). Inverse variance weighting (IVW) was applied as the primary analysis method. The weighted median, MR-Egger, simple model, and weighted model were used as complementary analysis methods to assess causal effects. Moreover, heterogeneity was analyzed using Cochran's Q-test with IVW and MR-Egger. The MR-Egger intercept and MR-PRESSO analysis methods were used for pleiotropy testing. The stability of the results was also assessed using a leave-one-out analysis.ResultsIn the discovery stage, the IVW approach revealed an odds ratio (OR) of 1.207 with a 95% confidence interval (CI) of 1.027–1.417 and a P-value of 0.022. This suggests a causal association between IS levels and an increased risk of FS. In the subtype studies of IS, the findings were negative. However, during the replication stage, a significant causal link was found between selected lacunar strokes and FS with an OR of 1.252, a 95% CI of 1.105–1.419, and a P-value of 0.0004. All studies had no pleiotropy or heterogeneity, and the findings were robust.ConclusionsOur study confirmed the causal relationship between any IS level and increased risk of FS. Furthermore, the same results were obtained in the replication stage with lacunar stroke as an exposure factor. However, there was no direct causal relationship between the subtypes of IS and FS. Our study provides theoretical support for shoulder care for patients with IS.

Background: Notch receptors (Notch 1/2/3/4), the critical effectors of the Notch pathway, participate in the tumorigenesis and progression of many malignancies. However, the clinical roles of Notch receptors in primary glioblastoma (GBM) have not been fully elucidated.Methods: The genetic alteration-related prognostic values of Notch receptors were determined in the GBM dataset from The Cancer Genome Atlas (TCGA). Two GBM datasets from TCGA and Chinese Glioma Genome Atlas (CGGA) were used to explore the differential expression between Notch receptors and IDH mutation status, and GBM subtypes. The biological functions of Notch Receptors were explored by Gene Ontology and KEGG analysis. The expression and prognostic significance of Notch receptors were determined in the TCGA and CGGA datasets and further validated in a clinical GBM cohort by immunostaining. A Notch3-based nomogram/predictive risk model was constructed in the TCGA dataset and validated in the CGGA dataset. The model performance was evaluated by receiver operating curves, calibration curves, and decision curve analyses. The Notch3-related phenotypes were analyzed via CancerSEA and TIMER. The proliferative role of Notch3 in GBM was validated in U251/U87 glioma cells by Western blot and immunostaining.Results: Notch receptors with genetic alterations were associated with poor survival of GBM patients. Notch receptors were all upregulated in GBM of TCGA and CGGA databases and closely related to the regulation of transcription, protein-lysine N-methyltransferase activity, lysine N-methyltransferase activity, and focal adhesion. Notch receptors were associated with Classical, Mesenchymal, and Proneural subtypes. Notch1 and Notch3 were closely correlated with IDH mutation status and G-CIMP subtype. Notch receptors displayed the differential expression at the protein level and Notch3 showed a prognostic significance in a clinical GBM cohort. Notch3 presented an independent prognostic role for primary GBM (IDH1 mutant/wildtype). A Notch3-based predictive risk model presented favorable accuracy, reliability, and net benefits for predicting the survival of GBM patients (IDH1 mutant/wildtype and IDH1 wildtype). Notch3 was closely related to immune infiltration (macrophages, CD4+ T cells, and dendritic cells) and tumor proliferation.Conclusion: Notch3-based nomogram served as a practical tool for anticipating the survival of GBM patients, which was related to immune-cell infiltration and tumor proliferation.

Objective: Cervical squamous cell carcinoma (CESC) is a cancer with high mortality caused by human papillomavirus. The aim of this study was to uncover potential CESC biomarkers to help early diagnosis and treatment. Materials and methods: The mRNA transcriptome data and DNA methylation data were downloaded from database for the identification of differentially expressed mRNAs (DEmRNAs) and DNA methylation analysis. Functional analysis was used to reveal the molecular functions. Then, the association between differential methylation and DEmRNA was analyzed. Protein–protein interaction (PPI) network analysis was performed on the selected differentially methylated genes (DEGs). Subsequently, we analyzed the prognosis and constructed a prognostic risk model. We also performed diagnostic analyses of risk model genes. In addition, we verified the protein expression level of identified DEGs. Results: 1438 DEmRNAs, 1669 differentially methylated sites (DMSs), 46 differentially methylated CpG islands and 53 differential methylation genes (DMGs) were obtained. In PPI, the highest interaction scores were MX2 and IRF8, and their interaction score was 0.928. Interestingly, 5 DMGs were found to be associated with CESC prognosis. In addition, our results demonstrated that high risk score was associated with poor prognosis of CESC. Furthermore, it was found that ZIK1, ZNRF2, HHEX, VCAM1 could be diagnostic molecular markers for CESC. Conclusion: Analysis of methylated-differentially expressed genes may contribute to the identification of early diagnosis and therapeutic targets of CESC. In addition, a prognostic model based on 5 DMGs can be used to predict the prognosis of CESC.

Background The yearly prevalence of metabolic syndrome (MS) is increasing in China. Although the level of serum uric acid (SUA) is closely related to MS, due to the influence of renal function on SUA, standardized SUA 〔SUA/serum creatinine ratio (SUA/Scr) 〕 may be a better predictor for MS. Visceral adiposity index (VAI) , as an important indicator for estimating visceral fat accumulation, could be used to predict MS more directly. However, few studies have explored whether VAI mediates the association between SUA/Scr ratio and MS in euthyroid population. Objective To explore the mediating effect of VAI on SUA/Scr ratio and MS in people with normal thyroid function. Methods A total of 10 042 annual health examinees were selected from the Health Examination Center, Hebei General Hospital from January 2020 to June 2021. The basic demographic information, physical examination and biochemical parameters, as well as calculated SUA/Scr ratio and VAI were collected. MS was diagnosed according to the criteria recommended by Chinese Diabetes Society. The risk of MS was analyzed by quartiles of SUA/Scr ratio (Q1-Q4 quartiles) , and VAI (V1-V4 quartiles) , respectively. Pearson correlation analysis was used to explore the association between SUA/Scr ratio and VAI. Multivariate Logistic regression analysis was used to explore the association of SUA/Scr ratio and VAI with MS. Bootstrap was used to explore whether VAI mediated the association between SUA/Scr ratio and MS. Results Of the 10 042 participants, 1 833 (18.25%) had MS and 8 209 (81.75%) did not. Pearson correlation analysis showed that SUA/Scr ratio was positively associated with VAI (P

Next-Generation Sequencing (NGS) allows rapid analysis of multiple genes for the detection of clinically actionable variants. This study reports the analytical validation of a targeted pan cancer NGS panel CANSeqTMKids for molecular profiling of childhood malignancies. Analytical validation included DNA and RNA extracted from de-identified clinical specimens including formalin fixed paraffin embedded (FFPE) tissue, bone marrow and whole blood as well as commercially available reference materials. The DNA component of the panel evaluates 130 genes for the detection of single nucleotide variants (SNVs), Insertion and Deletions (INDELs), and 91 genes for fusion variants associated with childhood malignancies. Conditions were optimized to use as low as 20% neoplastic content with 5 ng of nucleic acid input. Evaluation of the data determined greater than 99% accuracy, sensitivity, repeatability, and reproducibility. The limit of detection was established to be 5% allele fraction for SNVs and INDELs, 5 copies for gene amplifications and 1,100 reads for gene fusions. Assay efficiency was improved by automation of library preparation. In conclusion, the CANSeqTMKids allows for the comprehensive molecular profiling of childhood malignancies from different specimen sources with high quality and fast turnaround time.

Abstract Objective To study the value of multitime point salivary pepsin testing (MTPSPT) for the diagnosis of laryngopharyngeal reflux (LPR). Study Design Prospective noncontrolled. Methods For patients who met the enrollment criteria, the reflux symptom index (RSI) and reflux finding score (RFS) were calculated and salivary pepsin testing was performed. The pepsin test was performed every hour from 7:00 a.m. to 6:00 p.m. by collecting fresh saliva samples. A single positive test result was needed for the diagnosis of LPR. The consistency in the diagnosis of LPR between the two methods was compared with the weighted Cohen's kappa statistic. Results A total of 204 patients were included. The kappa value between the two methods was 0.566 (p = .00). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of MTPSPT were 76.43%, 85.94%, 92.24%, and 62.5%, respectively. We also compared a single pepsin measure at 7 a.m. with the screening results based on the RSI and RFS, and found a much lower kappa agreement value (0.223, p = .00). The sensitivity, specificity, PPV, NPV, and false‐negative rate of pepsin testing at 7 a.m. (fasting) were 37.86%, 92.18%, 91.38%, 40.41%, and 58.57%, respectively. Conclusion The use of the result of a single salivary pepsin test in the morning yields a relatively higher rate of missed diagnosis of LPR, and multitime point testing through a day increased the accuracy and sensitivity of detection of LPR twofold compared to a single morning fasting sample. Level of Evidence 3

IntroductionSubarachnoid hemorrhage (SAH) is a severe hemorrhagic stroke with high mortality. However, there is a lack of clinical tools for predicting in-hospital mortality in clinical practice. LAR is a novel clinical marker that has demonstrated prognostic significance in a variety of diseases.MethodsCritically ill patients diagnosed and SAH with their data in the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database and the eICU Collaborative Research Database (eICU-CRD) were included in our study. Multivariate logistic regression was utilized to establish the nomogram.ResultsA total of 244 patients with spontaneous SAH in the MIMIC-IV database were eligible for the study as a training set, and 83 patients in eICU-CRD were included for external validation. Data on clinical characteristics, laboratory parameters and outcomes were collected. Univariate and multivariate logistic regression analysis identified age (OR: 1.042, P-value: 0.003), LAR (OR: 2.592, P-value: 0.011), anion gap (OR: 1.134, P-value: 0.036) and APSIII (OR: 1.028, P-value: < 0.001) as independent predictors of in-hospital mortality and we developed a nomogram model based on these factors. The nomogram model incorporated with LAR, APSIII, age and anion gap demonstrated great discrimination and clinical utility both in the training set (accuracy: 77.5%, AUC: 0.811) and validation set (accuracy: 75.9%, AUC: 0.822).ConclusionLAR is closely associated with increased in-hospital mortality of patients with spontaneous SAH, which could serve as a novel clinical marker. The nomogram model combined with LAR, APSIII, age, and anion gap presents good predictive performance and clinical practicability.

BackgroundThe chromobox family, a critical component of epigenetic regulators, participates in the tumorigenesis and progression of many malignancies. However, the roles of the CBX family members (CBXs) in glioblastoma (GBM) remain unclear.MethodsThe mRNA expression of CBXs was analyzed in tissues and cell lines by Oncomine and Cancer Cell Line Encyclopedia (CCLE). The differential expression of CBXs at the mRNA level was explored in The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases with the “beeswarm” R package. The protein expression of CBXs in GBM was further examined on Human Protein Atlas (HPA). The correlations between CBXs and IDH mutation and between CBXs and GBM subtypes were investigated in the TCGA portal and CGGA database with the “survminer” R package. The alteration of CBXs and their prognostic value were further determined via the cBioPortal and CGGA database with the “survival” R package. The univariate and multivariate analyses were performed to screen out the independent prognostic roles of CBXs in the CGGA database. Cytoscape was used to visualize the functions and related pathways of CBXs in GBM. U251 and U87 glioma cells with gene intervention were used to validate the role of CBX7/8 in tumor proliferation and invasion. Proliferation/invasion-related markers were conducted by Western blot and immunostaining.ResultsCBXs presented significantly differential expressions in pan-cancers. CBX2/3/5/8 were upregulated, whereas CBX6/7 were downregulated at mRNA level in GBM of TCGA and CGGA databases. Similarly, high expression of CBX2/3/5 and low expression of CBX6/8 were further confirmed at the protein level in the HPA. CBX2/6/7 were positively correlated with IDH mutation and CBX1/2/4/5/8 were closely related to GBM subtypes. CBX7 and CBX8 presented the independent prognostic factors for GBM patient survival. GO and KEGG analyses indicated that CBXs were closely related to the histone H3-K36, PcG protein complex, ATPase, and Wnt pathway. The overexpression of CBX7 and underexpression of CBX8 significantly inhibited the proliferation and invasion of glioma cells in vivo and in vitro.ConclusionOur results suggested that CBX7 and CBX8 served as independent prognostic indicators that promoted the proliferation and invasion of glioma cells, providing a promising strategy for diagnosing and treating GBM.

BackgroundThe association between free triiodothyronine/free thyroxine (FT3/FT4) and non-alcoholic fatty liver disease (NAFLD) in euthyroid subjects is unclear. In addition, few studies have explored whether VAI mediates the association between FT3/FT4 ratio and NAFLD in the euthyroid population. We aimed to analyze the mediating effect of VAI on the FT3/FT4 ratio and NAFLD risk in the euthyroid population.MethodsThis cross-sectional study included 7 946 annual health examinees from the Health Examination Center, Hebei General Hospital, from January to December 2020. The basic information and biochemical parameters, as well as calculated FT3/FT4 ratio and VAI were collected. NAFLD was diagnosed according to abdominal ultrasonography. The fibrosis score for NAFLD positive subjects (NFS) was calculated to reflect the extent of liver fibrosis. The risk of NAFLD was analyzed by quartiles of FT3/FT4 ratio (Q1-Q4 quartiles) and VAI (V1-V4 quartiles), respectively. Pearson correlation analysis was performed to investigate the correlation between FT3/FT4 ratio and VAI. Multivariate logistic regression analysis was applied to analyze the effect of FT3/FT4 ratio and VAI on NAFLD and NFS status. Bootstrap was conducted to explore whether VAI mediated the association between FT3/FT4 ratio and NAFLD.ResultsOf the 7 946 participants, 2 810 (35.36%) had NAFLD and 5 136 (64.64%) did not. Pearson correlation analysis indicated that FT3/FT4 ratio was positively associated with VAI (P

Abstract The methyltransferase EZH2 plays an important role in regulating chromatin conformation and gene transcription. Phosphorylation of EZH2 at S21 by AKT kinase suppresses its function. However, protein phosphatases responsible for the dephosphorylation of EZH2‐S21 remain elusive. Here, it is demonstrated that EZH2 is highly expressed in the ocular lens, and AKT‐EZH2 axis is important in TGFβ‐induced epithelial‐mesenchymal transition (EMT). More importantly, it is identified that MYPT1/PP1 dephosphorylates EZH2‐S21 and thus modulates its functions. MYPT1 knockout accelerates EMT, but expression of the EZH2‐S21A mutant suppresses EMT through control of multiple families of genes. Furthermore, the phosphorylation status and gene expression modulation of EZH2 are implicated in control of anterior subcapsular cataracts (ASC) in human and mouse eyes. Together, the results identify the specific phosphatase for EZH2‐S21 and reveal EZH2 dephosphorylation control of several families of genes implicated in lens EMT and ASC pathogenesis. These results provide important novel information in EZH2 function and regulation.

The long-term effectiveness of targeted cancer therapies is limited by the development of resistance. Although epigenetic reprogramming has been implicated in resistance, the mechanisms remain elusive. Herein, we demonstrate that increased chromatin accessibility is involved in adaptive BRAF inhibitor (BRAFi)-resistance in melanoma cells. We observed loss of chromatin assembly factor 1 (CAF-1) and its related histone H3 lysine 9 trimethylation (H3K9me3) with adaptive BRAFi resistance. We further showed that depletion of CAF-1 provides chromatin plasticity for effective reprogramming by AP1 components to promote BRAFi resistance. Our data suggest that therapeutic approaches to restore H3K9me3 levels may compensate for the loss of CAF-1 and, in turn, suppress resistance to BRAF inhibitors.

For high-speed mobile orthogonal frequency division multiplexing (OFDM) systems, a novel time-varying channel prediction method based on deep learning was proposed.To avoid the influence caused by random initialization of network parameters, the proposed method firstly obtains an ideal channel estimation based on data and pilot, and then pre-trains the back propagation (BP) neural network based on the channel estimation to obtain the ideal network initial parameters.Then, based on the initial network value obtained by pre-training, the proposed method uses the channel estimation based on pilot to train the BP neural network again.Finally, the proposed method realizes the single-time-and multi-time prediction of time-varying channels through on-line prediction.Simulation results show that the proposed method can significantly improve the prediction accuracy of time-varying channels and has a low computational complexity.

Purpose. To investigate the association of the A/G rs1014290 polymorphism in SLC2A9 with type 2 diabetes (T2DM) and prediabetes mellitus (pre-DM). Patients and Methods. We enrolled 1058 patients who attended the Hebei General Hospital, Shijiazhuang, Hebei Province, China. The patients underwent general testing and oral glucose tolerance tests and were divided into three groups: 352 patients newly diagnosed with T2DM, 358 patients with pre-DM, and 348 healthy controls. The single nucleotide polymorphism (SNP) was detected by ligase detection reactions. The χ2 test, one-way ANOVA, and binary logistic regression analysis were used to analyze the results. Results. In the T2DM group, the GG genotype frequency at the rs1014290 locus was significantly lower (14.8%) than it was in the healthy controls. Furthermore, the GG genotype group was associated with a reduced risk of T2DM in unadjusted and confounder-adjusted models compared with the risk in the AA genotype group. The G allele in the SLC2A9 rs1014290 locus decreased susceptibility to T2DM. In the pre-DM group, the GG and AG genotype groups had no significant correlation with the risk of pre-DM in any of the models. In the T2DM group, the uric acid level was significantly lower in the GG genotype group. In the T2DM and pre-DM groups, the HOMA-β levels were significantly higher in the GA (P

Protein sumoylation is one of the most important post-translational modifications regulating many biological processes (Flotho A & Melchior F. 2013. Ann Rev. Biochem. 82:357–85). Our previous studies have shown that sumoylation plays a fundamental role in regulating lens differentiation (Yan et al., 2010. PNAS, 107(49):21034-9.; Gong et al., 2014. PNAS. 111(15):5574–9). Whether sumoylation is implicated in lens pathogenesis remains elusive. Here, we present evidence to show that the protein inhibitor of activated STAT-1 (PIAS1), a E3 ligase for sumoylation, is implicated in regulating stress-induced lens pathogenesis. During oxidative stress-induced cataractogenesis, expression of PIAS1 is significantly altered at both mRNA and protein levels. Upregulation and overexpression of exogenous PIAS1 significantly enhances stress-induced apoptosis. In contrast, silence of PIAS1 with CRISPR/Cas9 technology attenuates stress-induced apoptosis. Mechanistically, different from other cells, PIAS1 has little effect to activate JNK but upregulates Bax, a major proapoptotic regulator. Moreover, Bax upregulation is derived from the enhanced transcription activity of the upstream transcription factor, p53. As revealed previously in other cells by different laboratories, our data also demonstrate that PIAS1 promotes SUMO1 conjugation of p53 at K386 residue in lens epithelial cells and thus enhances p53 transcription activity to promote Bax upregulation. Silence of Bax expression largely abrogates PIAS1-mediated enhancement of stress-induced apoptosis. Thus, our results demonstrated that PIAS1 promotes oxidative stress-induced apoptosis through positive control of p53, which specifically upregulates expression of the downstream proapoptotic regulator Bax. As a result, PIAS1-promoted apoptosis induced by oxidative stress is implicated in lens pathogenesis.

Animals utilize conserved mechanisms to regulate oxidative stress. The C. elegans SKN-1 protein is homologous to the vertebrate Nrf (NF-E2-related factor) family of cap ’n’ collar (CnC) transcription factors and functions as a core regulator of xenobiotic and oxidative stress responses. The WD40 repeat-containing protein WDR-23 is a key negative regulator of SKN-1 activity. We previously found that the oxidative stress induced by excess iodide can be relieved by loss of function in the BLI-3/TSP-15/DOXA-1 dual oxidase complex. To further understand the molecular mechanism of this process, we screened for new mutants that can survive in excess iodide and identified gain-of-function mutations in skn-1 and loss-of-function mutations in wdr-23. The SKN-1C isoform functions in the hypodermis to affect animal’s response to excess iodide, while the SKN-1A isoform appears to play a minor role. wdr-23(lf) can interact with bli-3 mutations in a manner different from skn-1(gf). Transcriptome studies suggest that excess iodide causes developmental arrest largely independent of changes in gene expression, and wdr-23(lf) could affect the expression of a subset of genes by a mechanism different from SKN-1 activation. We propose that WDR-23 and SKN-1 coordinate with the BLI-3/TSP-15/DOXA-1 dual oxidase complex in response to iodide-triggered oxidative stress.

Interactions between neighboring cells often occur in a semiconductor silicon detector array. That is, there are high-energy particles incident on one cell of the detector that generate an electric signal for the cell, while weak signals are also generated in other neighboring cells. Therefore, isolation of the detector cells is an important factor in the performance of the detector, particularly for its energy resolution. To eliminate the dead space in the 3D-trench-electrode detector proposed by Brookhaven National Laboratory, a novel three-dimensional (3D) detector, the 3D-Open-Shell-Electrode Detector (3DOSED), was proposed in 2018, in which good isolation between cells was achieved. To verify this and determine the optimal structure design, a Silvaco technology computer-aided design simulation tool was used to simulate the electrical characteristics of the detector in 3D. The distributions of the electric field and the weighting field of 3DOSEDs were obtained with different opening gap angles. A single minimum ionizing particle was used that was incident vertically on the middle of the central collection electrode and peripheral trench electrode of the detector cell, according to the Ramo theorem of the principle of induced-current generation, and the mathematical software matlab was employed to calculate the induced current and carrier drift time. The interference current between the neighboring cells of a 3DOSED was obtained. Good isolation was found between neighboring cells in the 3DOSED.

Abstract The handheld ultrasound demonstrates clinical and economic value in combating COVID-19 based on interviews with frontline ultrasound physician and cardiologist as well as a national expert in medical ultrasound.

Cataract is a leading ocular disease causing global blindness. The mechanism of cataractogenesis has not been well defined. Here, we demonstrate that the heat shock protein 90β (HSP90β) plays a fundamental role in suppressing cataractogenesis. HSP90β is the most dominant HSP in normal lens, and its constitutive high level of expression is largely derived from regulation by Sp1 family transcription factors. More importantly, HSP90β is significantly down-regulated in human cataract patients and in aging mouse lenses, whereas HSP90β silencing in zebrafish causes cataractogenesis, which can only be rescued by itself but not other HSP90 genes. Mechanistically, HSP90β can directly interact with CHMP4B, a newly-found client protein involved in control of cytokinesis. HSP90β silencing causes upregulation of CHMP4B and another client protein, the tumor suppressor p53. CHMP4B upregulation or overexpression induces excessive division of lens epithelial cells without proper differentiation. As a result, these cells were triggered to undergo apoptosis due to activation of the p53/Bak-Bim pathway, leading to cataractogenesis and microphthalmia. Silence of both HSP90β and CHMP4B restored normal phenotype of zebrafish eye. Together, our results reveal that HSP90β is a critical inhibitor of cataractogenesis through negative regulation of CHMP4B and the p53-Bak/Bim pathway. [ABSTRACT FROM AUTHOR]